Our Patent WO 9962884 describes new derivatives of Δ2-pyrazolines, also known as 4,5-dihydro-1H-pyrazoles, which inhibit the enzyme cyclooxygenase-2, with application in human and/or veterinary medicine as anti-inflammatories and in other diseases in which cyclooxygenase-2 is involved, and which present a low or zero gastric and renal toxicity, so that they are anti-inflammatories with a greater safety profile. Certain racemic mixtures (±)—1, and the enantiomerically pure stereoisomers (−)-1 and (+)-1 described in said Patent are currently in a clinical investigation stage. The aforementioned Patent describes the preparation of (±)-1 by reaction of (E)-1,1,1-trifluoro-4-aryl-3-buten-2-one with 4-(aminosulphonyl)phenylhydrazine or 4-(methylsulphonyl)phenylhydrazine, or by reaction of 4-(aryl)phenylhydrazine with (E)-1,1,1-trifluoro-4-(4-aminosulphonylphenyl)-3-buten-2-one or (E)-1, 1,1-trifluoro-4-(4-methylsulphonylphenyl)-3-buten-2-one. It also describes the production of (−)-1 and (+)-1 by resolution of the racemic mixture (±)-1 using high resolution liquid chromatography with a CHIRALPAK AS column of de 10μ particle size and dimensions 25×2 cm (Daicel), mobile phase 0.1% of diethylamine in methanol and flow rate of 8 ml/min.
In addition, the methods for resolution of racemic mixtures described in the literature are numerous and have been widely used [a) for a monograph of the properties of racemates and their resolutions see Jacques, Collet, Wilen “Enantiomers Racemates and Resolutions”, Wiley: New York, 1981; for reviews see: b) Wilen, Top. Stereochem., 1971, 6, 107; c) Boyle, Q. Rev. Chem. Soc., 1971, 25; d) Buss, Vermeulen, Ind. Eng. Chem., 1968, 60, 12]. However, there are few examples in the scientific literature regarding resolution of A2—pyrazolines [Toda, J. Chem. Soc., Chem. Commun., 1995, 1453]. This paper describes the resolution of a Δ2-pyrazoline by formation of an inclusion complex. A prior paper [Mukai, Can. J. Chem., 1979, 57, 360–366] develops the resolution of an optically active assembly of Δ2-pyrazolines-sodium benzenosulphate from the corresponding racemics, using as resolution agents cinconidine, (−)-α-methylbenzylamine and brucine, depending on the substrate. This method has the disadvantage of using successive recrystallisations in both the process of formation of sodium sulphonate (between 3 and 7 recrystallisations), and in the process of formation and separation of the mixture of diastereoisomeric salts (between 4 and 7 recrystallisations), which results in a considerable reduction of the yield.
We have now found a strategy for preparing compounds with the general formula 1 which consists of using derivatives of benzaldehyde much cheaper than 4-(aminosulphonyl)benzaldehyde or 4-(methylsulphonyl)benzaldehyde for obtaining (E)-1,1,1-trifluoro-4-aryl-3-buten-2-one, and derivatives of phenylhydrazine much cheaper than 4-(aminosulphonyl)phenylhydrazine or 4-(methylsulphonyl)phenylhydrazine. The enone and hydrazine are used to obtain the ring of Δ2-pyrazoline, which process when sequentially combined with a sulphonation and an optical resolution process to obtain the enantiomerically pure compounds of the racemic sulphonic acid using an optically active base, or a mixture of bases in which at least one is optically active, leads to the formation of diastereoisomeric salts. The process continues with the separation of these salts, transformation into the sodium salt, formation of the acid chloride and obtaining the enantiomerically pure sulphonamide or sulphone 1.
The present invention provides a method of preparing the racemic mixture of the compound with formula (±)-1, wherein                each of R1 and R3 which may be the same or different is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, trifluoromethyl and methoxy; and        each of R2 and R4 which may be the same or different is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, methylsulphonyl and aminosulphonyl;        with the condition that one of the substituents R2 or R4 is a methylsulphonyl or aminosulphonyl group;        method comprising preparing the racemic mixture with the general formula (±)-1 by:        (a) reacting an (E)-1,1,1-trifluoro-4-aryl-3-buten-2-one (formula 2) with a phenylhydrazine (formula 3),         wherein each of R1 and R3, which may be the same or different is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, trifluoromethyl and methoxy;        and each of R2 and R4 which may be the same or different is selected from the group consisting of hydrogen, chlorine, fluorine, a methyl, trifluoromethyl, methoxy and trifluoromethoxy group;        with the condition that at least one of the substituents R2 or R4 is a hydrogen;        in order to obtain a pyrazoline with the general formula (±)-4,         wherein each of R1 and R3 which may be the same or different is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, trifluoromethyl and methoxy; and        each of R2 and R4 which may be the same or different is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, trifluoromethyl, methoxy and trifluoromethoxy;        with the condition that at least one of the substituents R2 or R4 is a hydrogen;        (b) reacting the compound of formula (±)-4 with chlorosulphonic acid to form a pyrazoline with the formula (±)-5, wherein each of R1 and R3 which may be the same or different is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, trifluoromethyl and methoxy; and        each of R2 and R4 which may be the same or different is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, trifluoromethyl, methoxy, trifluoromethoxy and sulphonyl chloride,        with the condition that one of the substituents R2 or R4 is a sulphonyl chloride group (SO2Cl);        or alternatively reacting the compound of formula (±)-4 with chlorosulphonic acid followed by reaction with sodium hydroxide to form the pyrazoline with the formula (±)-6,         wherein each of R1 and R3, which may be the same or different is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, trifluoromethyl and methoxy group, and        each of R2 and R4 which may be the same or different is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, trifluoromethyl, methoxy, trifluoromethoxy and sodium sulphonate group,        with the condition that one of the substituents R2 or R4 represents a sodium sulphonate group (SO3Na);        (c) reacting the pyrazoline of either the formula (±)-5 or the formula (±)-6 with thionyl chloride to form the pyrazoline with the formula (±)-7, wherein each of R1 and R3, which may be the same or different is selected from the group consisting of hydrogen, chlorine, fluorine, a methyl, trifluoromethyl and methoxy: and        each of R2 and R4 which may be the same or different is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, trifluoromethyl, methoxy, trifluoromethoxy and sulphonyl chloride,        with the condition that one of the substituents R2 or R4 represents a sulphonyl chloride group (SO2Cl); and        (d) reacting the pyrazoline with the formula (±)-7 with one compound selected from the group consisting of ammonium carbonate, ammonia, sodium sulphite combined with methyl iodide and methyl sulphate resulting in the racemic mixture of the compound with formula (±)-1.        